Interleukin‐12 as a target for modulation of the inflammatory response in asthma

Wills‐Karp, Marsha

doi:10.1111/j.1398-9995.1998.tb03858.x

Cited by 31 publications

(15 citation statements)

References 58 publications

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“…IL-12 is important in the initial phase of bacterial, parasitic, and viral infections; and stimulates the development of the Th1-type immune response, while inhibiting differentiation of Th2 cells [Trinchieri and Gerosa, 1996;Wills-Karp, 1998]. Th1 cells produce, among others, IFN-g, which has direct antiviral activity in vitro and is also a strong inhibitor of the Th2 cytokine response [Boehm et al, 1997].…”

Section: Introductionmentioning

confidence: 99%

Respiratory syncytial virus enhances respiratory allergy in mice despite the inhibitory effect of virus‐induced interferon‐γ

Barends

Boelen

Rond

et al. 2002

Journal of Medical Virology

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In mice, respiratory syncytial virus (RSV) infection during allergic provocation aggravates the allergic Th2 immune response, characterised by production of interleukin (IL)-4, IL-5, and IL-13, and eosinophilic inflammation. This enhancement of the Th2 response occurs simultaneously with a strong RSV-induced Th1 cytokine response (IL-12 and IFN-gamma). The present study investigated whether IFN-gamma and IL-12 are critically involved in this RSV-enhanced OVA allergy. Therefore, IFN-gammaR- and IL-12-deficient mice (both on a 129/Sv/Ev background) were sensitised and challenged with ovalbumin (OVA) and infected with RSV during the OVA challenge period. Neither gene deletion affected the development of ovalbumin-induced allergic inflammation in mice. However, when OVA-allergic IFN-gammaR deficient mice were infected with RSV, an increased pulmonary eosinophilic infiltrate and increased IL-4 and IL-13 mRNA expression in lung tissue were observed compared with identically treated wild-type mice. In contrast, deficiency of IL-12 did not aggravate the Th2 immune and inflammatory response in OVA/RSV-treated mice, compared with wild-type. In conclusion, the virus-induced IFN-gamma response diminishes the Th2 inflammatory response during OVA allergy but fails to prevent totally the enhancement of the OVA allergy by RSV. In contrast, IL-12 is not involved in inhibiting nor increasing the RSV-enhanced allergy in 129/Sv/Ev mice.

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Section: Introductionmentioning

confidence: 99%

Respiratory syncytial virus enhances respiratory allergy in mice despite the inhibitory effect of virus‐induced interferon‐γ

Barends

Boelen

Rond

et al. 2002

Journal of Medical Virology

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“…IL-12, in fact, through the induction of IFN-␥ secretion, induces the development of Th1-type immune responses. IL-12 is also a costimulus for activated T and NK cells and enhances the cytolytic activity of NK and T cells (13,(19)(20)(21). IL-10, on the other hand, by inhibiting IFN-␥, indirectly promotes the commitment of Th0 cells to the Th2 phenotype, even though it may also inhibit IL-4 and IL-5, key cytokines of the Th2 pattern (10).…”

Section: Discussionmentioning

confidence: 99%

Normal Human Lung Fibroblasts Differently Modulate Interleukin-10 and Interleukin-12 Production by Monocytes

Vancheri

Mastruzzo

Tomaselli

et al. 2001

Am J Respir Cell Mol Biol

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The ability of lung fibroblasts to modulate the immune response has been evaluated by analyzing the synthesis and release of interleukin (IL)-10 and IL-12 by lipopolysaccharide (LPS)-stimulated peripheral blood monocytes exposed to pulmonary fibroblast conditioned medium (FCM). IL-10 and IL-12 contents and gene expression were markedly modified by treatment with FCM as measured by ELISA (+97.5 +/- 12.8% and -68 +/- 7.3% for IL-10 and IL-12, respectively), immunocytochemistry, and reverse transcriptase-polymerase chain reaction (RT-PCR). These effects appeared to be mediated by prostaglandin E(2) (PGE(2)) as the modified release of both cytokines was reduced by treatment with indomethacin and mimicked by addition of exogenous PGE(2.) As a result of the enhanced production of IL-10, exposure of LPS/interferon (IFN)-gamma-activated monocytes to FCM was also able to reduce the expression of the class II major histocompatibility complex (MHC) molecule, human leukocyte-associated antigen-DR (HLA-DR) (-51.8 +/- 8.7%) and of the costimulatory molecule, CD40 (-53.9 +/- 11.7%). The expression of both molecules was completely restored when monocytes were pretreated with a neutralizing anti-IL-10 monoclonal antibody. The FCM obtained from fibrotic lung fibroblasts was instead less efficacious in potentiating LPS-stimulated IL-10 release and, consequently, in reducing HLA-DR and CD40 expression, suggesting that an impairment of the immune regulation operated by fibroblasts may be involved in the maintenance of chronic pulmonary inflammation.

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“…The major drawback with currently available asthma therapy is that inhaled ␤ 2 -agonists and steroids are palliative, providing temporary symptomatic relief, but are not curative. However, the natural history of asthma, frequently with childhood onset and the patient "growing out" of the disease, illustrates the potential for pharmacologic disease modification by immunomodulation [75]. Recombinant human IL-12 (Roche and Genetics Institute) has the capacity to alter the balance in T lymphocyte populations, decreasing T H 2 cells that mediate allergic disease and increasing T H 1 cells [76].…”

Section: Interleukin-12mentioning

confidence: 99%

Novel drugs for treating asthma

Hansel

Barnes

2001

Curr Allergy Asthma Rep

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The health burden of asthma is increasing globally at an alarming rate, providing a strong impetus for the development of new therapeutics, particularly drugs that may prevent development of the disease. Currently available inhaled bronchodilators and anti-inflammatory drugs are effective in most asthmatic patients, but this palliative therapy requires long-term daily administration. Despite considerable efforts by the pharmaceutical industry, it has been difficult to develop novel therapeutic agents, the leukotriene antagonists being the only new class of asthma treatments to be licensed in the past 30 years. It is clearly important to understand more about the underlying mechanisms of asthma and about how currently used drugs work before rational improvements in therapy can be expected. There are numerous therapies in clinical development that combat the inflammation found in asthma, specifically targeting eosinophils, IgE, adhesion molecules, cytokines (interleukin-4, -5, -13) and chemokines, inflammatory mediators, and cell signaling (kinase inhibitors). In particular, there is the obvious need for new therapy for severe asthma that is poorly controlled by high-dose corticosteroids as well as agents to counter acute emergency asthma. A long-term goal is to develop disease-modifying immunotherapy that could be introduced in childhood to alter the natural history of asthma. Thanks to the extensive efforts of the pharmaceutical industry, we can expect the introduction of a range of novel therapies for asthma in the near future.

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Interleukin‐12 as a target for modulation of the inflammatory response in asthma

Cited by 31 publications

References 58 publications

Respiratory syncytial virus enhances respiratory allergy in mice despite the inhibitory effect of virus‐induced interferon‐γ

Respiratory syncytial virus enhances respiratory allergy in mice despite the inhibitory effect of virus‐induced interferon‐γ

Normal Human Lung Fibroblasts Differently Modulate Interleukin-10 and Interleukin-12 Production by Monocytes

Novel drugs for treating asthma

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